Piperazine benzothiazoles as agents for the treatment of cerebral ischemic disorders or cns disorders

ABSTRACT

The present invention is related to piperazine henzothiazole derivatives, notably for use in the treatment and/or prophylaxis of cerebral ischemic disorders or CNS disorders. The present invention is furthermore related to methods of their preparation.

FIELD OF THE INVENTION

The present invention is related to piperazine benzothiazolederivatives, notably for use in the treatment and/or prophylaxis ofcerebral ischemic disorders or CNS disorders. The present invention isfurthermore related to methods of their preparation.

BACKGROUND OF THE INVENTION

Mammalian cells respond to some extracellular stimuli by activatingsignaling cascades which are mediated by various mitogen-activatedprotein kinases (MAPKs). Despite the differences in their response toupstream stimuli, the MAP kinase cascades are organized in a similarfashion, consisting of MAP kinase kinase kinases (MAPKKK or MEKK), MAPkinase kinases (MAPKK or MKK) and MAP kinases (MAPK). MAP kinases area-broad family of kinases which includes c-Jun N-Terminal kinases(JNKs), also known as “stress-activated protein kinases” (SAPKs), aswell as extracellular signal regulated kinases (ERKs) and p38 MAPkinases. Each of these three MAP kinases sub-families is involved in atleast three different but parallel pathways conveying the informationtriggered by external stimuli. The JNK signaling pathway is activated byexposure of cells to environmental stress—such as chemical toxins,radiation, hypoxia and osmotic shock—as well as by treatment of cellswith growth factors or pro-inflammatory cytokines—such as tumournecrosis factor alpha (TNF-(α) or interleukin-1 beta (IL-1β).

Two MAP kinase kinases (known as MKKs or MAPKKs), i.e. MKK4 (known alsoas JNKK1) and MKK7, activate JNK by a dual phosphorylation of specificthreonine and tyrosine residues located within a Thr-Pro-Tyr motif onthe activation loop on the enzyme, in response to cytokines and stresssignals. Even further upstream in the signaling cascade, MKK4 is knownto be activated itself also by a MAP kinase kinase kinase, MEKK1 throughphosphorylation at serine and threonine residues.

Once activated, JNK binds to the N-terminal region of transcriptionfactor targets and phosphorylates the transcriptional activation domainsresulting in the up-regulation of expression of various gene products,which can lead to apoptosis, inflammatory responses or oncogenicprocesses (1).

Some transcription factors known to be JNK substrates are the Junproteins (c-jun, JunB and Jun D), the related transcription factors ATF2and ATFa, Ets transcription factors such as Elk-1 and Sap-1, the tumorsuppressor p53 and a cell death domain protein (DENN).

Three distinct JNK enzymes have been identified as products of the genesJNK1, JNK2 and JNK3 and ten different isoforms of JNK have beenidentified (2). JNK1 and −2 are ubiquitously expressed in human tissues,whereas JNK3 is selectively expressed in the brain, heart and testes(2). Each isoform binds to the substrates with different affinities,suggesting, in vivo, a substrate specific regulation of the signalingpathways by the different JNK isoforms.

Activation of the JNK pathway has been documented in a number of diseaseprocesses, thus providing a rationale for targeting this pathway fordrug discovery. In addition, molecular genetic approaches have validatedthe pathogenic role of this pathway in several diseases.

For example, auto-immune and inflammatory diseases derive from theinappropriate activation of the immune system. Activated immune cellsexpress many genes encoding inflammatory molecules, including cytokines,growth factors, cell surface receptors, cell adhesion molecules anddegradative enzymes. Many of these genes are known to be regulated bythe JNK pathway, through the activation of the transcription factorsc-Jun and ATF-2.

The inhibition of JNK activation in bacteriallipopolysaccharide-stimulated macrophages, effectively modulates theproduction of the key pro-inflammatory cytokine, TNFα (3).

The inhibition of JNK activation decreases the transcription factoractivation responsible of the inducible expression of matrixmetalloproteinases (MMPs) (4), which are known to be responsible of thepromotion of cartilage and bone erosion in rheumatoid arthritis and ofgeneralized tissue destruction in other auto-immune diseases.

The JNK cascade is also activated in T cells by antigen stimulation andCD28 receptor co-stimulation (5) and regulates the production of theIL-2 promoter (6). Inappropriate activation of T lymphocytes initiatesand perpetuates many auto-immune diseases, including asthma,inflammatory bowel syndrome and multiple sclerosis.

In neurons vulnerable to damage from Alzheimer's disease and in CA1neurons of patients with acute hypoxia (7), JNK3 protein is highlyexpressed. The JNK3 gene was also found, to be expressed in the damagedregions of the brains of Alzheimer's patients (8). In addition, neuronsfrom JNK3 KO mice were found to become resistant to kainic acid inducedneuronal apoptosis compared to neurons from wild-type mice.

Based on these findings, the JNK signaling pathway and especially thatof JNK2 and JNK3, is thought to be implicated in apoptosis-drivenneurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease, epilepsy and seizures, Huntington's disease, CNS disorders,traumatic brain injuries as well as ischemic disorders and hemorrhagingstrokes.

Several small molecules have been proposed as modulators of the JNKpathway (WO 00/35909; WO 00/35906; WO 00/3592, WO 00/64872, WO 01/12609,WO 00/75118, WO 01/12621).

WO 01/47920 discloses benzothiazole derivatives as JNK inhibitors offormula (A).

A general problem in the treatment of CNS disorders, e.g. cerebraldisorders, is the transport of the therapeutic compounds into the CNSsystem, e.g. to the brain. It is well known that the BBB impedes thedelivery of drugs to the CNS.

The Blood-Brain Barrier (BBB) is a barrier, made up of capillary wallsand surrounding neuroglia, that limits the passages of substancesbetween the blood and brain tissue.

The Blood-Brain Barrier (BBB) maintains a homeostatic environment in thecentral nervous system (CNS). The capillaries that supply the blood tothe brain have tight junctions which block passage of most moleculesthrough the capillary endothelial membranes. While the membranes doallow passage of lipid soluble materials, such as heroin and otherpsychoactive drugs, water soluble materials such as glucose, proteinsand amino acids do not pass through the BBB. Mediated transportmechanisms exist to transport-glucose and essential amino acids acrossthe BBB. Active transport mechanisms remove molecules which become inexcess, such as potassium, from the brain. For a general review seeGoldstein and Betz, 1986 and Betz et al, 1994, incorporated herein intheir entirety by reference (14; 15).

SUMMARY OF THE INVENTION

The present invention is related to piperazine benzothiazolederivatives, notably for use in the treatment and/or prophylaxis ofcerebral ischemic disorders or CNS disorders. The present invention isfurthermore related to methods of their preparation.

DESCRIPTION OF THE INVENTION

The following paragraphs provide definitions of the various chemicalmoieties that make up the compounds according to the invention and areintended to apply uniformly throughout the specification and claimsunless an otherwise expressly set out definition provides a broaderdefinition.

“C₁-C₆-alkyl” refers to monovalent alkyl groups having 1 to 6 carbonatoms. This term is exemplified by groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl and thelike.

“Aryl” refers to an unsaturated aromatic carbocyclic group of from 6 to14 carbon atoms having a single ring (e.g., phenyl) or multiplecondensed rings (e.g. naphthyl). Preferred aryl include phenyl,naphthyl, phenantrenyl and the like.

“C₁-C₆-alkyl aryl” refers to C₁-C₆-alkyl groups having an arylsubstituent, including benzyl, phenethyl and the like.

“Heteroaryl” refers to a monocyclic heteroaromatic, or a bicyclic or atricyclic fused-ring heteroaromatic group. Particular examples ofheteroaromatic groups include optionally substituted pyridyl, pyrrolyl,furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadia-zolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl,[2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl,isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl,imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxa-zolyl, quinolizinyl,quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl,pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl,quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl,5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl,xanthenyl or benzoquinolyl.

“C₁-C₆-alkyl heteroaryl” refers to C₁-C₆-alkyl groups having aheteroaryl substituent, including 2-furylmethyl, 2-thienylmethyl,2-(1H-indol-3-yl)ethyl and the like.

“C₂-C₆-alkenyl” refers to alkenyl groups preferably having from 2 to 6carbon atoms and having at least 1 or 2 sites of alkenyl unsaturation.Preferable alkenyl groups include ethenyl (—CH═CH₂), n-2-propenyl(allyl, —CH₂CH═CH₂) and the like.

“C₂-C₆-alkenyl aryl” refers to C₂-C₆-alkenyl groups having an arylsubstituent, including 2-phenylvinyl and the like.

“C₂-C₆-alkenyl heteroaryl” refers to C₂-C₆-alkenyl groups having aheteroaryl substituent, including 2-(3-pyridinyl)vinyl and the like.

“C₂-C₆-alkynyl” refers to alkynyl groups preferably having from 2 to 6carbon atoms and having at least 1-2 sites of alkynyl unsaturation,preferred alkynyl groups include ethynyl (—C≡CH), propargyl (—CH₂C≡CH),and the like.

“C₂-C₆-alkynyl aryl” refers to C₂-C₆-alkynyl groups having an arylsubstituent, including phenylethynyl and the like.

“C₂-C₆-alkynyl heteroaryl” refers to C₂-C₆-alkynyl groups having aheteroaryl substituent, including 2-thienylethynyl and the like.

“C₃-C₈-cycloalkyl” refers to a saturated carbocyclic group of from 3 to8 carbon atoms having a single ring (e.g, cyclohexyl) or multiplecondensed rings (e.g. norbornyl). Preferred cycloalkyl includecyclopentyl, cyclohexyl, norbornyl and the like.

“Heterocycloalkyl” refers to a C₃-C₈-cycloalkyl group according to thedefinition above, in which up to 3 carbon atoms are replaced byheteroatoms chosen from the group consisting of O, S, NR, R beingdefined as hydrogen or methyl. Preferred heterocycloalkyl includepyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine, andthe like.

“C₁-C₆-alkyl cycloalkyl” refers to C₁-C₆-alkyl groups having acycloalkyl substituent, including cyclohexylmethyl, cyclopentylpropyl,and the like.

“C₁-C₆-alkyl heterocycloalkyl” refers to C₁-C₆-alkyl groups having aheterocycloalkyl substituent, including 2-(1-pyrrolidinyl)ethyl,4-morpholinylmethyl, (1-methyl-4-piperidinyl)methyl and the like.

“Carboxy” refers to the group —C(O)OH.

“C₁-C₆-alkyl carboxy” refers to C₁-C₅-alkyl groups having an carboxysubstituent, including 2-carboxyethyl and the like.

“Acyl” refers to the group —C(O)R where R includes “C₁-C₆-alkyl”,“aryl”, “heteroaryl”, “C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”.

“C₁-C₆-alkyl acyl” refers to C₁-C₆-alkyl groups having an acylsubstituent, including 2-acetylethyl and the like.

“Acyloxy” refers to the group —OC(O)R where R includes “C₁-C₆-alkyl”,“aryl”, “hetero-aryl”, “C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”.

“C₁-C₆-alkyl acyloxy” refers to C₁-C₆-alkyl groups having an acyloxysubstituent, including 2-(acetyloxy)ethyl and the like.

“Alkoxy” refers to the group —O—R where R includes “C₁-C₆-alkyl” or“aryl” or “hetero-aryl” or “C₁-C₆-alkyl” or “C₁-C₆-alkyl heteroaryl”.Preferred alkoxy groups include by way of example, methoxy, ethoxy,phenoxy and the like.

“C₁-C₆-alkyl alkoxy” refers to C₁-C₅-alkyl groups having an alkoxysubstituent, including 2-ethoxyethyl and the like.

“Alkoxycarbonyl” refers to the group —C(O)OR where R includes H,“C₁-C₆-alkyl” or “aryl” or “heteroaryl” or “C₁-C₆-alkyl aryl” or“C₁-C₆-alkyl heteroaryl”.

“C₁-C₆-alkyl alkoxycarbonyl” refers to C₁-C₆-alkyl groups having analkoxycarbonyl substituent, including 2-(benzyloxycarbonyl)ethyl and thelike.

“Aminocarbonyl” refers to the group —C(O)NRR′ where each R, R′ includesindependently hydrogen or C₁-C₆-alkyl or aryl or heteroaryl or“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl hetero-aryl”.

“C₁-C₆-alkyl aminocarbonyl” refers to C₁-C₆-alkyl groups having anaminocarbonyl substituent, including 2-(dimethylaminocarbonyl)ethyl andthe like.

“Acylamino” refers to the group —NRC(O)R′ where each R, R′ isindependently hydrogen or “C₁-C₆-alkyl” or “aryl” or “heteroaryl” or“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”.

“C₁-C₆-alkyl acylamino” refers to C₁-C₆-alkyl groups having an acylaminosubstituent, including 2-(propionylamino)ethyl and the like.

“Ureido” refers to the group —NRC(O)NR′R″ where each R, R′, R″ isindependently hydrogen or “C₁-C₆-alkyl” or “aryl” or “heteroaryl” or“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl” “cycloalkyl” or“heterocycloalkyl”, and where R′ and R″, together with the nitrogen atomto which they are attached, can optionally form a 3-8-memberedheterocycloalkyl ring.

“C₁-C₆-alkyl ureido” refers to C₁-C₅-alkyl groups having an ureidosubstituent, including 2-(N′-methylureido)ethyl and the like.

“Amino” refers to the group —NRR′ where each R,R′ is independentlyhydrogen or “C₁-C₆-alkyl” or “aryl” or “heteroaryl” or “C₁-C₆-alkylaryl” or “C₁-C₆-alkyl heteroaryl”, or “cycloalkyl”, or“heterocycloalkyl”, and where R and R′, together with the nitrogen atomto which they are attached, can optionally form a 3-8-memberedheterocycloalkyl ring.

“C₁-C₆-alkyl amino” refers to C₁-C₅-alkyl groups having an aminosubstituent, including 2-(1-pyrrolidinyl)ethyl and the like.

“Ammonium” refers to a positively charged group —N⁺RR′R″, where eachR,R′,R″ is independently “C₁-C₆-alkyl” or “C₁-C₆-alkyl aryl” or“C₁-C₆-alkyl heteroaryl”, or “cycloalkyl”, or “heterocycloalkyl”, andwhere R and R′, together with the nitrogen atom to which they areattached, can optionally form a 3-8-membered heterocycloalkyl ring.

“Halogen” refers to fluoro, chloro, bromo and iodo atoms.

“Sulfonyloxy” refers to a group —OSO₂—R wherein R is selected from H,“C₁-C₆-alkyl”, “C₁-C₆-alkyl” substituted with halogens, e.g., an—OSO₂—CF₃ group, “aryl”, “heteroaryl”, “C₁-C₆-alkyl aryl” or“C₁-C₆-alkyl heteroaryl”.

“C₁-C₆-alkyl sulfonyloxy” refers to C₁-C₆-alkyl groups having asulfonyloxy substituent, including 2-(methylsulfonyloxy)ethyl and thelike.

“Sulfonyl” refers to group “—SO₂—R″ wherein R is selected from H,“aryl”, “heteroaryl”, “C₁-C₆-alkyl”, “C₁-C₆-alkyl” substituted withhalogens, e.g., an —SO₂—CF₃ group, “C₁-C₆-alkyl aryl” or “C₁-C₆-alkylheteroaryl”.

“C₁-C₆-alkyl sulfonyl” refers to C₁-C₆-alkyl groups having a sulfonylsubstituent, including 2-(methylsulfonyl)ethyl and the like.

“Sulfinyl” refers to a group “—S(O)—R” wherein R is selected from H,“C₁-C₆-alkyl”, “C₁-C₆-alkyl” substituted with halogens, e.g., an —SO—CF₃group, “aryl”, “heteroaryl”, “C₁-C₆-alkyl aryl” or “C₁-C₆-alkylheteroaryl”.

“C₁-C₆-alkyl sulfinyl” refers to C₁-C₆-alkyl groups having a sulfinylsubstituent, including 2-(methylsulfinyl)ethyl and the like.

“Sulfinyl” refers to groups —S—R where R includes “C₁-C₆-alkyl” or“aryl” or “hetero-aryl” or “C₁-C₆-alkyl aryl” or “C₁-C₆-alkylheteroaryl”. Preferred sulfanyl groups include methylsulfanyl,ethylsulfanyl, and the like.

“C₁-C₆-alkyl sulfanyl” refers to C₁-C₆-alkyl groups having a sulfanylsubstituent, including 2-(ethylsulfanyl)ethyl and the like.

“Sulfonylamino” refers to a group —NRSO₂—R′ where each R, R′ isindependently hydrogen or “C₁-C₆-alkyl” or “aryl” or “heteroaryl” or“C₁-C₆-alkyl aryl” or “C₁C₆-alkyl heteroaryl”.

“C₁-C₆-alkyl sulfonylamino” refers to C₁-C₆-alkyl groups having asulfonylamino substituent, including 2-(ethylsulfonylamino)ethyl and thelike.

“Substituted or unsubstituted”: Unless otherwise constrained by thedefinition of the individual substituent, the above set out groups, like“alkyl”, “alkenyl”, “alkynyl”, “aryl” and “heteroaryl” etc. groups canoptionally be substituted with from 1 to 5 substituents selected fromthe group consisting of “C₁-C₆-alkyl”, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”,“cycloalkyl”, “heterocycloalkyl”, “C₁-C₆-alkyl aryl”, “C₁-C₆-alkylheteroaryl”, “C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkyl heterocycloalkyl”,“amino”, “ammonium”, “acyl”, “acyloxy”, “acylamino”, “aminocarbonyl”,“alkoxycarbonyl”, “ureido”, “aryl”, “heteroaryl”, “sulfinyl”,“sulfonyl”, “alkoxy”, “sulfanyl”, “halogen”, “carboxy”, trihalomethyl,cyano, hydroxy, mercapto, nitro, and the like. Alternatively saidsubstitution could also comprise situations where neighbouringsubstituents have undergone ring closure, notably when vicinalfunctional substituents are involved, thus forming, e.g., lactams,lactons, cyclic anhydrides, but also acetals, thioacetals, aminalsformed by ring closure for instance in an effort to obtain a protectivegroup.

“Pharmaceutically acceptable salts or complexes” refers to salts orcomplexes of the below-identified compounds of formulae (I) and (II)that retain the desired biological activity. Examples of such saltsinclude, but are not restricted to acid addition salts formed withinorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuricacid, phosphoric acid, nitric acid, and the like), and salts formed withorganic acids such as acetic acid, oxalic acid, tartaric acid, succinicacid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoicacid, tannic acid, pamoic acid, alginic acid, polyglutamic acid,naphthalene sulfonic acid, naphthalene disulfonic acid, andpoly-galacturonic acid. Said compounds can also be administered aspharmaceutically acceptable quaternary salts known by a person skilledin the art, which specifically include the quarternary ammonium salt ofthe formula —NR,R′,R″⁺Z, wherein R, R′, R″ is independently hydrogen,alkyl, or benzyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkylaryl, C₁-C₆-alkyl heteroaryl, cycloalkyl, heterocycloalkyl, and Z is acounterion, including chloride, bromide, iodide, —O-alkyl,toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate(such as benzoate, succinate, acetate, glycolate, maleate, malate,fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, anddiphenylacetate).

“Pharmaceutically active derivative” refers to any compound that uponadministration to the recipient, is capable of providing directly orindirectly, the activity disclosed herein.

“Enantiomeric excess” (ee) refers to the products that are obtained byan asymmetric synthesis, i.e. a synthesis involving non-racemic startingmaterials and/or reagents or a synthesis comprising at least oneenantioselective step, whereby a surplus of one enantiomer in the orderof at least about 52% ee is yielded.

Said formula also comprises its tautomers, its geometrical isomers, itsoptically active forms as enantiomers, diastereomers and its racemateforms, as well as pharmaceutically acceptable salts thereof. Preferredpharmaceutically acceptable salts of the formula (I) are acid additionsalts formed with pharmaceutically acceptable acids like hydrochloride,hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate,acetate, benzoate, succinate, fumarate, maleate, lactate, citrate,tartrate, gluconate, methanesulfonate, benzenesulfonate, andpara-toluenesulfonate salts.

The compounds according to the present invention are those of formula I.

R in formula (I) is selected from the group comprising or consisting ofhydrogen, substituted or unsubstituted C₁-C₆-alkyl, substituted orunsubstituted C₁-C₆-alkyl aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted C₁-C₆-alkyl heteroaryl, substituted orunsubstituted C₂-C₆-alkenyl, substituted or unsubstituted C₂-C₆-alkenylaryl, substituted or unsubstituted C₂-C₆-alkenyl heteroaryl, substitutedor unsubstituted C₂-C₆-alkynyl, substituted or unsubstitutedC₂-C₆-alkynyl aryl, substituted or unsubstituted C₂-C₆-alkynylheteroaryl, substituted or unsubstituted C₃-C₈-cycloalkyl, substitutedor unsubstituted heterocycloalkyl, substituted or unsubstitutedC₁-C₆-alkyl cycloalkyl, substituted or unsubstituted C₁-C₆-alkylheterocycloalkyl, substituted or unsubstituted C₁-C₆-alkyl carboxy,acyl, substituted or unsubstituted C₁-C₆-alkyl acyl, acyloxy,substituted or unsubstituted C₁-C₆-alkyl acyloxy, substituted orunsubstituted C₁-C₆-alkyl alkoxy, alkoxycarbonyl, substituted orunsubstituted C₁-C₆-alkyl alkoxycarbonyl, aminocarbonyl, substituted orunsubstituted C₁-C₆-alkyl aminocarbonyl, acylamino, substituted orunsubstituted C₁-C₆-alkyl acylamino, ureido, substituted orunsubstituted C₁-C₆-alkyl ureido, amino, substituted or unsubstitutedC₁-C₆-alkyl amino, sulfonyloxy, substituted or unsubstituted C₁-C₆-alkylsulfonyloxy, sulfonyl, substituted or unsubstituted C₁-C₆-alkylsulfonyl, sulfinyl, substituted or unsubstituted C₁-C₆-alkyl sulfinyl,sulfanyl, substituted or unsubstituted C₁-C₆-alkyl sulfanyl,sulfonylamino, substituted or unsubstituted C₁-C₆-alkyl sulfonylamino.

R¹ is selected from the group comprising or consisting of H, halogen,cyano, nitro, amino, substituted or unsubstituted C₁-C₆-alkyl, inparticular C₁-C₃ alkyl, like methyl or ethyl or —CF₃, substituted orunsubstituted C₂-C₆-alkenyl, substituted or unsubstituted C₂-C₆-alkynyl,substituted or unsubstituted C₁-C₆-alkyl-aryl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl,substituted or unsubstituted C₁-C₆-alkyl-heteroaryl, —C(O)—OR²,—C(O)—R², —C(O)—NR²R^(2′), —(SO₂)R², with

R² and R^(2′) being independently selected from the group comprising orconsisting of hydrogen, unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or substitutedC₂-C₆ alkynyl, unsubstituted or substituted aryl, unsubstituted orsubstituted heteroaryl, unsubstituted or substituted C₁-C₆-alkyl aryl,unsubstituted or substituted C₁-C₆-alkyl heteroaryl. Preferably R¹ is H.

n is an integer from 0 to 3, more preferred is 1.

According to a more preferred embodiment piperazine benzothiazolederivative according to the present invention are those wherein R ishydrogen, C₁-C₃ alkyl, aminocarbonyl, C₁-C₆-alkyl alkoxycarbonyl,C₁-C₆-alkyl alkoxy, C₁-C₆-alkyl acyloxy, alkoxycarbonyl, C₁-C₆-alkylaminocarbonyl. Specifically, R H, or C₁-C₃ alkyl, in particular a methylor an ethyl moiety, or C₁-C₆-alkyl alkoxy.

The present invention also comprises the corresponding tautomers havingthe following formula:

Specific piperazine benzothiazole derivatives according to the presentinvention are selected from the following group:

-   -   1,3-benzothiazol-2-yl[2-({4-[(4-methylpiperazin-1-yl)methyl]benzyl}oxy)pyrimidin-4-yl]acetonitrile    -   1,3-benzothiazol-2-yl[2-({4-[(4-benzyl-piperazin-1-yl)methyl]-benzyl}oxy)pyrimidin-4-yl]acetonitrile    -   1,3-benzothiazol-2-yl(2-{[4-(piperazin-1-ylmethyl)benzyl]oxy}pyrimidin-4yl)acetonitrile    -   1,3-benzothiazol-2-yl[2-({4-[(4-formylpiperazin-1-yl)methyl]benzyl}oxy)pyrimidin-4-yl]acetonitrile    -   [2-({4-[(4-acetylpiperazin-1-yl)methyl]benzyl}oxy)pyrimidin-4-yl](1,3-benzothiazol-2-yl)acetonitrile    -   (3H-Benzothiazol-2-ylidene)-{2-[4-(4-[1,2,4]oxadiazol-3-ylmethyl-piperazin-1-ylmethy)-benzyloxy]-pyrinmidin-4-yl}-acetonitrile    -   4-(4-{4-[(3H-Benzothiazol-2-ylidene)-cyano-methyl]-pyrimidin-2-yloxymethyl}-benzyl)-piperazine-1-carboxylic        acid methyl ester    -   2-[4-(4-{4-[(3H-Benzotiazol-2-ylidene)-cyano-methyl]-pyrimidin-2-yloxymethyl}-benzyl)-piperazin-1-yl]-acetamide    -   (2-{4-[4-(2-Amino-acetyl)-piperazin-1-ylmethyl]-benzyloxy}-pyrimidin-4yl)-(3H-benzothiazol-2-ylidene)-acetonitrile    -   [4-(4-{4-[(3H-Benzothiazol-2-ylidene)-cyano-methyl]-pyrimidin-2-yloxymethyl}3-benzyl)-piperazin-1-yl]-acetic        acid methyl ester    -   (3H-Benzothiazol-2-ylidene)-(2-{4-[4-(2-methoxy-ethyl)-piperazin-1-ylmethyl]-benzyloxy}-pyrimidin-4yl)-acetonitrile    -   4-(4-{4-[(3H-Benzothiazol-2-ylidene)-cyano-methyl]-pyrimidin-2-yloxymethyl}-benzyl)-piperazine-1-carboxylic        acid dimethylamide    -   (3H-Benzothiazol-2-ylidene)-{2-[4-(4-ethyl-piperazin-1-ylmethyl)-benzyloxy]-pyrimidin-4-yl}-acetonitrile    -   (3H-Benzothiazol-2-yliden)-(2-{4-[4-(2-hydroxy-ethyl)-piperazin-1-ylmethyl]-benzyloxy}-pyrimidin-4-yl)-acetonitrile

The present invention also includes the geometrical isomers, the opticalactive forms, enantiomers, diastereomers of compounds according toformula I, as well as their racemates and also pharmaceuticallyacceptable salts, as well as the pharmaceutically active piperazinebenzothiazole derivatives of formula I.

The compounds of the present invention are inhibitors of JNKs, inparticular of JNK3 and may therefore be used in the treatment ofdisorders mediated by JNKs. Surprisingly, the compounds of the presentinvention show a considerable capacity to cross the blood-brain barrier(BBB) and are therefore particularly useful in the treatment of cerebralischemic disorders or CNS disorders. Hence, a further aspect of thepresent invention consists in the use of the piperazine benzothiazolederivatives of the present invention in the treatment and/or prophylaxisof cerebral ischemic disorders or CNS disorders.

A further aspect of the present invention is related to the use of thepiperazine benzothiazole derivatives according to formula I or II forthe preparation of pharmaceutical compositions for the treatment ofcerebral ischemic disorders or CNS disorders.

Still a further object of the present invention is a process forpreparing the novel benzo-thiazole derivatives according to formulae Ior II. A general synthetic access to the compounds according to formulaI is set out in scheme I.

As illustrated in the above scheme I, the starting compounds of formulaIII are reacted with (suitably substituted (activated) pyrimidines),like halogeno pyrimidines, e.g. 2,4-dichloro-pyrimidine of formula VI toprovide the pyrimidino-benzothiazole compounds IV. Preferably suchreactions are performed in the presence of suitable bases, e.g. sodiumhydride, potassium hydride and the like in an anhydrous inertatmosphere, preferably in a polar solvent like DMF, DMA, MeCN or THF ata temperature in the range of about −78° C. to 100° C.

Benzothiazbles of formula m are either commercially available, such asfrom Maybridge Chemical Co. Ltd or can be prepared from commerciallyavailable compounds by conventional procedures.

Halogenated pyrimidines, e.g. 2,4-dichloropyrimidine of formula VI, arealso either commercially available, such as from Aldrich, Fluka, Sigmaand the like or may be prepared by conventional procedures.

For obtaining the final piperazine benzothiazoles of formula (I), theintermediate compounds of formula (IV) are preferably reacted withsuitable alcohols of formula (V), as illustrated in scheme II.

The reaction is preferably performed in the presence of solvents such asDMF, DMA, NMP, DMSO or ACN, most preferably in DMA or MeCN, in thepresence of a suitable base such as tBuOK, CS2CO3 (Cesiumcarbonate) withor without CuI, NaH, or the like, most preferably NaH, at a temperaturein the range of about 25 to 120° C. In a preferred method, the startingcompounds are heated at 25° up to 100° C. in solution in DMA in thepresence of NaH.

The intermediate compounds of formula (V) may be obtained by a syntheticapproach which is illustrated in scheme III. In said scheme III thestaring building block is methyl-p-toluate to prepare a benzyl alcohol.In the case of a phenethylalcohol or a phenylpropyl alcohol according toformula (V), methyl-p-toluate may be replaced by the appropriatestarting materials, commercially available or prepared by conventionalmethods.

As used herein, “treating” refers to inhibiting or arresting thedevelopment of a disease, disorder or condition and/or causing thereduction, remission or regression of the symptoms of a disease,disorder or condition. Those of skill in the art will understand thatvarious methodologies and assays may be used to assess the developmentof a disease, disorder or condition, and similarly, variousmethodologies and assays may be used to assess the reduction, remissionor regression of the symptoms of a disease, disorder or condition.

When employed as pharmaceuticals, the piperazine benzothiazolederivatives of the present invention are typically administered in theform of a pharmaceutical composition. Hence, pharmaceutical compositionscomprising a compound of formula I and a pharmaceutically acceptablecarrier, diluent or excipient therefore are also within the scope of thepresent invention. A person skilled in the art is aware of a wholevariety of such carrier, diluent or excipient compounds suitable toformulate a pharmaceutical composition. Also, the present inventionprovides compounds for use as a medicament.

The compounds of the invention, together with a conventionally employedadjuvant, carrier, diluent or excipient may be placed into the form ofpharmaceutical compositions and unit dosages thereof, and in such formmay be employed as solids, such as tablets or filled capsules, orliquids such as solutions, suspensions, emulsions, elixirs, or capsulesfilled with the same, all for oral use, or in the form of sterileinjectable solutions for parenteral (including subcutaneous use). Suchpharmaceutical compositions and unit dosage forms thereof may compriseingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

The pharmaceutical compositions of these inventions can be administeredby a variety of routes including oral, rectal, transdermal,subcutaneous, intravenous, intramuscular; intrathecal, intraperitonealand intranasal. Depending on the intended route of delivery, thecompounds are preferably formulated as either injectable, topical ororal compositions. The compositions for oral administration may take theform of bulk liquid solutions or suspensions, or bulk powders. Morecommonly, however, the compositions are presented in unit dosage formsto facilitate accurate dosing. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient Typical unit dosageforms include prefilled, premeasured ampoules or syringes of the liquidcompositions or pills, tablets, capsules or the like in the case ofsolid compositions. In such compositions, the piperazine benzothiazolecompound is usually a minor component (from about 0.1 to about 50% byweight or preferably from about 1 to about 40% by weight) with theremainder being various vehicles or carriers and processing aids helpfulfor forning the desired dosing form.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatine; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art. As above mentioned, the piperazine benzothiazole derivativesof formula I in such compositions-is typically a minor component,frequently ranging between 0.05 to 10% by weight with the remainderbeing the injectable carrier and the like.

The above-described components for orally administered or injectablecompositions are merely representative. Further materials as well asprocessing techniques and-the like are set out in Part 8 of Remington'sPharmaceutical Sciences, 17^(th) Edition, 1985, Marck PublishingCompany, Easton, Pa., which is incorporated herein be reference.

The compounds of this invention can also be administered in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can also befound in the incorporated materials in Remington's PharmaceuticalSciences.

In the following the present invention shall be illustrated by means ofsome examples which are not construed to be viewed as limiting the scopeof the invention.

In the following the present invention shall be illustrated by means ofsome examples which are not construed to be viewed as limiting the scopeof the invention.

The HPLC, NMR and MS data provided in the examples described below wereobtained as followed: HPLC: column Waters Symmetry C850×4.6 mm,Conditions: a—MeCN/H₂O 0.09% TFA, 0 to 100% (10 min); b—MeCN/H₂O, 5 to100% (8 min), max plot 230-400 nm; Mass spectra: PE-SCIEX API 150 EX(APCI and ESI), LC/MS spectra: Waters ZMD (ES); ¹H-NMR: Bruker DPX-300MHz.

The purifications were obtained as followed: Preparative HPLC WatersPrep LC 4000 System equipped with columns Prep Nova-Pak®HR C186 μm 60 Å,40×30 mm (up to 100 mg) or 40×300 mm (up to 1 g). All the purificationswere performed with a gradient of MeCN/H₂O 0.09% TFA.

EXAMPLE A Preparation of the Intermediate Compound (IV); (see Scheme 1)1,3-benzothiazol-2-yl(2-chloro-4-pyrimidinyl)-acetonitrile

To a stirred suspension of NaH (60% in oil, 9.2 g, 0.23 mol) in dry THF(200 ml) was added drop wise under inert atmosphere a solution of1,3-benzothiazol-2yl-acetonitrile (20 g, 0.15 mol) in dry THF (200 ml).After 1 h30 stirring at r.t., a solution of 2,4-dichloropyri-midine(17.1 g, 0.15 mol) in dry THF (200 ml) was added dropwise. The reactionmixture was allowed to stir under inert atmosphere at r.t. untilcomplete disappearance of the starting material. The reaction wasquenched by addition of water and the THF was evaporated. Water wasadded and the suspension was slightly acidified with aqueous HCl 1M. Theprecipitate obtained was filtered off and washed thoroughly with wateruntil neutral then with hexane to remove the oil. The crude solid wasdried under vacuum at 40° C., affording 28 g (84%) of the title compoundas a light brown powder: mp 246° C. dec.; MS: 286.8 (M+1); HPLC(Conditions a, 268 nm) 97%, rt.5.66 min; ¹HNMR (DMSO-d6) δ 13.25 (br s,1H, exchangeable), 8.09 (d, J=4.14 Hz, 1H), 7.90 (d, J=7.53 Hz, 1H),7.61 (d, J=7.92 Hz, 1H), 7.39-7.34 (m, 1H), 7.20-7.15 (m, 1H), 6.96 (brd, 1H). CHN analysis: C₁₃H₇ClN₄S: Calculated: C, 54.19%; H 2.4%; N19.45%; Found: C, 53.35%; H 2.77%; N 17.62%.

EXAMPLE B Preparation of the Intermediate Compound (Va), (see Scheme 3)(4-(4-methyl-piperazin-1-ylmethvl-phenyl)-methanol Step 1:Methyl-p-toluate

To a solution of p-toluic acid (175 g, 1.28 mol) in methanol (2 L) wasadded dropwise thionylchloride (612 g, 5.14 mol) under stiring at 5° C.The mixture was refluxed overnight, then the solvent evaporated. Theresidue obtained was treated with a 10% aqueous NaHCO₃ solution (pH˜8)The product was extracted with ethyl acetate, washed-with water anddried. The solvent was removed and the crude was purified by columnchromatography (pet ether/ethyl acetate) to give methyl-p-toluate ascolorless liquid (180 g, 93%).

Step 2: 4-Methoxy carbonyl benzyl bromide

To a mixture of methyl-p-toluate (180 g, 1.2 mol) and N-bromosuccimide(235 g, 1.32 mol) in CCl₄ (2 L) was added in portion benzoyl peroxide(18 g, 0.1 times) at 50° C. The mixture was refluxed for 5 h. Then themixture was allowed to cool down to 40° C. and the solid was filteredoff. The filtrate was concentrated to give 4-methoxy carbonyl benzylbromide (252 g, 91%) as light yellow liquid.

Step 3: N-methyl(4-Methoxycarbonylbenzyl)piperazine

To a solution of N-methyl piperazine (80 g, 0.91 mol) and triethylamine(232 g, 2.29 mol) in absolute alcohol (1750 ml) was added dropwise at 0°C. a solution of 4-methoxycarbonyl-benzyl bromide (252 g, 1.1034 mol) inabsolute alcohol (250 ml). The mixture was stirred overnight at RT. Thenthe mixture was concentrated and the residue obtained was taken up in1.5N HCl (3 L) then washed with diethyl ether (3 times) and ethylacetate. The solution was neutralized with a 10% aqueous NaOH solutionand basified up to pH=8 with a 10% aqueous NaHCO₃ solution. The productwas extracted with CHCl₃, washed with water and brine then dried overNa₂SO₄. The solvent was removed and the crude was purified by columnchromatography CHCl₃/MeOH to give N-methyl(4-methoxy carbonylbenzyl)piperazine (150 g, 70%) as a brown liquid.

Step 4: (4-(4-Methyl-piperazin-1-ylmethyl-phenyl)-methanol

To a mixture of LAH (36 g, 0.957 mol) in dry THF (1750 ml) was addeddropwise at 0° C. under N₂ a solution of N-(4-methoxycarbonyl benzyl)bromide (150 g, 0.638 mol) in dry TVF (250 ml). The mixture was stirredovernight at RT under N₂, then quenched with a 10% aqueous NaOHsolution. The solid was filtered off and the filtrate was concentrated.The residue was taken up in DCM (1 L) and washed with water. The solventevaporated to give N-methyl(4-hydroxymethylbenzyl)piperazine (96 g, 73%)as light yellow liquid.

M⁺(ES):221.2

¹H NMR (DMSO-d6) δ 7.26-7.19 (m, 4H), 5.11 (t, J=5.65 Hz, 1H), 4.45 (d,J=5.65 Hz, 2H), 3.40 (s, 2H), 3.39-2.20 (m, 8H), 2.12 (s, 3H)

In a similar way the following intermediate compounds may be obtained.

(3-(4-Methyl-piperazin-1-ylmethyl-phenyl)-methanol

¹H NMR (DMSO-d6) δ 7.27-7.11 (m, 4H), 5.17-5.13 (m, 1H), 4.48-4.46 (m,2H), 3.41 (s, 2H), 2.41-2.21 (m, 8H), 2.13 (s, 3H)

4-(4-Hydroxymethyl-benzyl)-piperazin-1-carboxylic acid tert-butyl ester

M⁺(ES): 307.2

¹H NMR (DMSO-d6) δ 7.27-7.21 (m, 4H), 5.12 (t, J=5.65 Hz, 1H), 4.46 (d,J=5.65 Hz, 2H), 3.43 (s, 2H), 3.28 (br t, 4H), 2.27 (t, J=4.9 Hz, 4H),1.40 (s, 9H).

{4-[(4-ethylpiperazin-1-yl)methyl]phenyl}methanol

Y=78%, M⁺(ES): 235.3;

¹H NMR (DMSO-d6) δ 7.26-7.19 (m, 4H), 5.12 (t, J=5.6 Hz, 1H), 4.46 (brd, 2H), 3.33 (s, 2H), 2.44-2.20 (m, 8H), 2.27 (q, J=7.2 Hz, 2H), 0.95(t, J=7.2 Hz, 3H).

(4-{[4-(2-methoxyethyl)piperazin-1-yl]methyl}phenyl)methanol

Y=66%, M⁺(ES): 265;

¹H NMR (DMSO-d6) δ 7.23-7.22 (m, 4H), 5.11 (t, J=5.7 Hz, 1H), 4.45 (brd, 2H), 3.40 (s, 2H), 3.38 (t, J=5.9 Hz, 2H), 3.20 (s, 3H), 2.42 (t,J=5.9 Hz, 2H), 2.48-2.25 (m, 8H).

(4-{[4-benzyl-piperazin-1-yl]methyl}phenyl)methanol; Y=78%, M+(ES): 297

EXAMPLE 1 Preparation of1,3-benzothiazol-2-yl[2-({4-[(4-methylpiperazin-1-yl)methyl]-benzyl}-oxy)pyrimidin-4yl]acetonitrile(trimesylate salt) (see Scheme 2)

To a suspension of NaH (60% in oil, 1.68 g, 69.75 mmol) in dry DMA (80ml) was added a solution of(4-(4-methyl-piperazin-1-ylmethyl-phenyl)-methanol (compound of formulaV in scheme 2) (7.68 g, 34.88 mmol) in dry DMA (80 ml). The resultingsuspension was stirred 1 h at r.t. under inert atmosphere. A solution ofIV (5 g, 17.44 mmol) in DMA (80 ml) was added drop wise and thesuspension was stirred at 100° C. under inert atmosphere. After 4 hoursthe reaction was cooled down and quenched by addition of water. Thesolvents were evaporated and the residue was taken up in water (100 ml).10 mL of EtOAc and cyclohexane were added to trap the residual oil fromNaH and the solution was stored at 4° C. for a day. The precipitateformed was filtered off and washed with water until neutral pH then withcyclohexane, affording 6.17 g of crude base.

3.5 g of the crude base was taken up in water (125 ml) and 1.25 ml ofmethane sulfonic acid was added. The solution was lyophilised to give anorange-yellow solid which was washed with ACN and dried under vacuum at30° C. to afford 4.99 g (Yield=66%) of the title compound as a yellowpowder.

M³¹ (ESI): 469.1; M⁺(ESI): 471.16; HPLC (Conditions b, max plot) %, rt.2.01 min.

¹H NMR (DMSO-d6) δ 10.30 (very br s, 1H), 8.06-8.03 (m, 2H), 7.82 (d,J=8.3 Hz, 1H), 7.76 (d, J=7.9 Hz, 2H), 7.69 (d, J=7.9 Hz, 2H), 7.56-7.51(m, 1H), 7.40-7.35 (m, 1H), 6.88 (br d, 1H), 5.82 (s, 2H), 4.52 (s, 2H),3.85-3.57 (m, 4H), 3.48-3.26 (m, 4H), 2.95 (s, 3H), 2.48 (s, 9H).

EXAMPLE 2 Preparation of1,3-benzothiazol-2-yl[2-({4-[(4-benzyl-piperazin-1-yl)methyl]-benzyl}oxy)pyrimidin-4-yl]acetonitrile(2Mes)

The title compound was obtained by performing the same protocol set outin the above example 1, whereby(4-(4-benzyl-piperazin-1-ylmethyl-phenyl)-methanol is used instead of(4-(4-methyl-piperazin-1-ylmethyl-phenyl)-methanol.

Y: 42%; M⁻(ESI) 545.7; M⁺(ESI) 547.2; HPLC (Conditions b, max plot)99.8%, rt. 2.52 min.

¹H NMR (DMSO-d6) δ 7.95-7.93 (m, 2H), 7.73 (d, J=7.9 Hz, 1H), 7.67-7.64(m, 2H), 7.56-7.40 (m, 8H), 7.29-7.24 (m, 1H), 6.75 (br d, 1H), 5.73 (s,2H), 4.45-4.15 (m, 4H), 3.60-3.30 (m, 4H), 3.25, 2.90 (m, 4H).

EXAMPLE 3 Preparation of(3H-Benzothiazol-2-ylidene)-{2-[4-(4-ethyl-piperazin-1-ylmethyl)-benzyloxy]-pyrimidin-4-yl}-acetonitrile

The title compound was obtained by performing the same protocols set outin the above example 1, whereby{4-[(4-ethylpiperazin-1-yl)methyl]phenyl}methanol is used instead of(4-(4-methyl-piperazin-1-ylmethyl-phenyl)-methanol.

Y=: 83%, M⁺(ES): 485.18; HPLC (Conditions b, max plot) 97.8%, rt. 2.06min.

¹H NMR (DMSO-d6) δ 7.95 (d, J=7.9 Hz, 1H), 7.90 (br d, 1H), 7.74 (d,J=7.9 Hz, 1H), 7.67 (d, J=7.9 Hz, 2H), 7.58 (d, J=7.9 Hz, 1H), 7.45-7.40(m, 1H), 7.30-7.24 (m, 1H), 6.73 (br d, 1H), 5.73 (s, 2H), 4.32 (s, 2H),4.42-4.23 (m, 2H), 3.76-3.38 (m, 4H), 3.32-2.89 (m, 4H), 1.21 (t, J=7.1Hz, 3H)

EXAMPLE 4 Preparation of(3H-Benzothiazol-2-ylidene)-(2-{4-[4-(2-methoxy-ethyl)-piperazin-1-ylmethyl]-benzyloxy}-pyrimidin-4-yl)-acetonitrile(3TFA)

The title compound was obtained by performing the same protocole set outin the above example 1 whereby(4-{[4-(2-methoxyethyl)piperazin-1-yl]methyl}phenyl)methanol is usedinstead of (4-(4-methyl-piperazin-1-ylmethyl-phenyl)-methanol.

Y=: 33%, M⁺(ES): 515.06; HPLC (Conditions b, max plot) 99.5%, rt. 2.10min.

¹H NMR (DMSO-d6) δ 7.93 (d, J=7.9 Hz, 1H), 7.87 (br d, 1H),7.74 (d,J=8.3 Hz, 1H), 7.63 (d, J=7.9 Hz, 2H), 7.50 (d, J=7.9 Hz, 2H), 7.44-7.39(m, 1H), 7.28-7.23 (m, 1H), 6.70 (br d, 1H), 5.71 (s, 2H), 4.10 (s, 2H),3.63-3.60 (m, 2) 3.50-2.90 (m, 13H).

EXAMPLE b 5 Preparation of1,3-benzothiazol-2-yl(2-{[4-piperazin-1-ylmethyl)benzyl]oxy}-pyrimidin-4-yl)acetonitrile(3TFA)

The title compound was obtained by performing the same protocole set outin the above example 1, whereby4-(4-Boc-piperazin-1-ylmethyl-phenyl)-methanol is used instead of(4-(4-methyl-piperazin-1-ylmethyl-phenyl)-methanol. Thus, a Bocprotected crude base is obtained.

The Boc protected crude base was taken up in a mixture of DCM/TFA (9:1)and stirred 2 hours at r.t. The DCM was evaporated at r.t. The residuewas triturated in ether then filtered off and dried under vacuum at r.t.ON (over night). After purification by preparative HPLC, the purefractions were gathered and lyophilised affording 3.03 g (34%) of thetitle compound as a yellow powder.

Y=34%; M⁻(ES) 455.2; M⁺(ES) 457.4; HPLC (Conditions b, max plot) 99.7%,rt. 1.98 min;

¹H NMR (DMSO-d6) δ 9.00 (br s, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.87 (br d,1H), 7.74 (d, J=7.9 Hz, 1H), 7.63 (d, J=7.9 Hz, 2H), 7.51 (d, J=7.9 Hz,2H), 7.45-7.39 (m, 1H), 7.28-7.23 (m, 1H), 6.72 (d, J=6.4 Hz, 1H), 5.71(s, 2H), 4.10 (s, 2H), 3.32-3.18 (m, 4H), 3.13-2.92 (m, 4H)

EXAMPLE 6 Preparation of1,3-benzothiazol-2-yl[2-({4-[(4-formylpiperazin-1-yl)methyl]-benzyl}oxy)pyrimidin-4-yl]acetomitrile(2TFA)

The Boc-deprotected crude base obtained in example 3 (0.6 g, 1.31 mmol)was suspended in 15 ml of methylformate in a sealed vessel. The reactionmixture was stirred at 40° C. for 15 days then cooled down to r.t. Theprecipitate formed was filtered off then washed with water and the crudeproduct was purified by preparative HPLC. The pure fractions weregathered and lyophilised affording 0.26 g of the title compound as ayellow powder.

Y=28%; M⁻(ES) 483.3; M⁺(ES) 485.5; HPLC (Conditions b, max plot) 99.7%,rt. 2.18 min.

¹H NMR (DMSO-d6) d 9.95 (br s, 1H), 8.03 (s, 1H), 7.93 (d, J=7.9 Hz, 1),7.96-7.84 (very br d, 1H), 7.73 (d, J=7.9 Hz, 1H), 7.68 (d, J=7.9 Hz,2H), 7.54 (d, J=7.9 Hz, 2H), 7.47-7.40 (m, 1H), 7.29-7.24 (m, 1H), 6.73(br d, 1H), 5.73 (s, 2H), 4.36 (s, 2H), 4.05-2.80 (m, 8H)

EXAMPLE 7 Preparation of(2-{4-[4-(2-Amino-acetyl)-pinerazin-1-ylmethyl]-benzyloxy}-pyrimidin-4-yl)-(3H-benzothiazol-2-ylidene)-acetonitrile(2Mes) (3TFA,

To a DMA solution (40 ml) of Boc-deprotected crude product (2.9 g, 3.65mmol) obtained in example 5 was added amberlyst A21 (0.7 g, 3.76 mmol)and the solution was stirred at r.t. for 20 min. The resin was filteredoff and to the filtrate were added a solution of Boc Glycine (0.74 g, 4mmol), HOBt (0.73 g, 5.47 mmol), EDC (1.05 g, 5.47 mmol) and DIPEA (1.9g, 14.6 mmol) in DMA (30 ml). The resulting solution was stirredovernight at r.t. After evaporation of the solvent under reducedpressure, the residue obtained was suspended in a mixture of MeOH andEtOAc and left overnight at 4° C. The precipitate was filtered off,washed with EtOAc and dried under vacuum at 40° C., affording 1.04 g ofthe title compound as a yellow solid.

Y=10%, M⁺(ES): 514.06; HPLC (Conditions b, max plot) 99.9%, rt. 2.00min.

¹H NMR (DMSO-d6) δ 8.13-8.02 (m, 2H), 7.94-7.91 (m, 2H), 7.73 (br d,1H), 7.67 (d, J=7.9 Hz, 2H), 7.54 (d, J=7.9 Hz, 2H), 7.45-7.40 (m, 1H),7.29-7.24 (m, 1H), 6.74 (br d, 1H), 5.74 (s, 2H), 4.34 (s, 2H), 3.89 (s,2H), 3.73-3.10 (m, 8H)

EXAMPLE 8 Preparation of[2-({4-[(4-acetylpiperazin-1-yl)methyl]benzl}oxy)pyrimidin-4-yl](1,3-benzothiazol-2-yl)acetonitrile(2TFA)

To a DMA solution (6 ml) of Boc-deprotected crude product (0.3 g, 0.66mmol) obtained in example 5 were added triethylamine (0.09 ml, 0.66mmol) and acetyl chloride (0.09 ml, 1.31 mmol) and the solution wasstirred 5 min at r.t. The reaction mixture was concentrated to neardryness and the residue obtained was purified by preparative, HPLC. Thepure fractions were gathered and lyophilised affording 0.1 g (21%) ofthe title compound as a yellow powder.

M⁻(ES) 496.9; M⁺(ES) 499.1; HPLC (Conditions b, max plot) 99%, rt. 2.19min.

¹H NMR (DMSO-d6) δ 10.05 (br s, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.93-7.84(very br d, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.67 (d, J=8 Hz, 2H), 7.54 (d,J=7.9 Hz, 2H), 7.45-7.39 (m; 1H), 7.29-7.24 (m, 1H), 6.72 (br d, 1H),5.73 (s, 2H), 4.36 (s, 2H), 4.02-3.87 (m, 1H), 3.42-2.75 (m, 7H), 2.01(s, 3H).

EXAMPLE 9 Preparation of4-(4-{4-[(3H-Benzothiazol-2-ylidene)-cyano-methyl]-pyrimidin-2-yloxymethyl{-benzyl)-piperazine-1-carboxylicacid dimethylamide (2TFA)

To a DMA solution (12 ml) of Boc-deprotected crude product (0.5 g, 0.63mmol) obtained in example 5 were added amberlyst A21 (1.12 g, 5.35 mmol)and dimethylcarbamoyl chloride (0.12 ml, 1.31 mmol) and the solution wasstirred at 0° C. for 1 h. As no product was formed, the solution waswarmed up to r.t. for 12 days to obtain a complete disappearance of thestarting material. Amberlyst was filtered off and water was added to thefiltrate. As no precipate was formed, the solvents were evaporated underreduced pressure and the residue was taken up in water and lyophilised.The residue obtained was purified by preparative HPLC. The purefractions were gathered and lyophilised affording 85 mg of the titlecompound as a yellow solid.

Y=18%, M⁺(ES): 528.09; HPLC (Conditions b, max plot) 98.9%, rt. 2.32min.

¹H NMR (DMSO-d6) δ 9.82 (very br s, 1H), 7.94-7.86 (m, 2H), 7.73 (d,J=7.9 Hz, 1H), 7.67 (d, J=7.9 Hz, 2H), 7.55 (d, J=7.9 Hz, 2H), 7.44-7.39(m, 1H), 7.28-7.23 (m, 1H), 6.72 (br d, 1H), 5.73 (s, 2H), 4.37 (s, 2H),3.65-3.48 (m, 2H), 3.32-3.18 (m, 2H), 3.11-2.90 (m, 4H), 2.74 (s, 6H)

In a similar way the following compound may be obtained.

4-(4-{4-[(3H-Benzothiazol-2-ylidene)-cyano-methyl]-pyrimidin-2-yloxymethyl}-benzyl)-piperazine-1carboxylicacid methyl ester (2TFA)

Y=32%, M⁺(ES): 514.85; HPLC (Conditions b, max plot) 99%, rt. 2.36 min.

¹H NMR (DMSO-d6) δ 7.94-7.91 (m, 2H), 7.73 (br d, 1H), 7.66 (d, J=7.9Hz, 7.9 Hz, 2H), 7.53 (d, J=7.9 Hz, 2H), 7.46-7.40 (m, 1H), 7.29-7.24(m, 2H), 6.73 (br d, 1H), 5.73 (s, 2H), 4.34 (s, 2H), 4.13-3.92 (m, 2H),3.63 (s, 3H), 3.60-2.94 (m, 6H)

EXAMPLE 10 Preparation of(3H-Benzothiazol-2-ylidene)-{2-[4-(4-[1,2,4]oxadiazol-3-ylmethyl-piperazin-1-ylmethyl)-berzyloxy]-pyrimidin-4-yl}-acetonitrile(3TFA)

To a DMA solution (10 ml) of Boc-deprotected crude product (0.5 g, 0.63mmol) obtained in example 5 was added amberlyst A21 (0.7 g, 3.76 mmol)and the solution was stirred at r.t. for 20 min. The resin was filteredoff and to the filtrate were added 3-(chloromethyl)-1,2,4-oxadiazole andpotassium carbonate. The resulting suspension was stirred at r.t. for 48h. Complete disappearance of the starting material was achieved after 3days stirring at r.t and the addition of 2.4 Eq of3-(chloromethyl)-1,2,4-oxadiazole. After filtration and removal of thesolvent under reduced pressure, the residue obtained was purified bypreparative HPLC. The pure fractions were gathered and lyophilisedaffording 110 mg of the title compound as a yellow solid.

Y=20%, M⁺(ES): 538.94; HPLC (Conditions b, max plot) 97%, rt. 2.31 min.

¹H NMR (DMSO-d6) δ 9.62 (s, 1H), 7.93-7.91 (m, 2H), 7.73 (d, J=7.9 Hz,1H), 7.65 (d, J=7.9 Hz, 2H), 7.53 (d, J=7.9 Hz, 2H), 7.44-7.39 (m, 1H),7.27-7.22 (m, 1H), 6.72 (br d, 1H), 5.72 (s, 2H), 4.32 (s, 2H), 3.85 (s,2H), 3.34-3.17 (m, 2H), 3.12-2.88 (m, 4H), 2.58-2.41 (m, 2H)

In a similar way the following compounds may be obtained.

(3H-Benzothiazol-2-ylidene)-(2-{4-[4-(2-hydroxy-ethyl)-piperazin-1-ylmethyl]-benzyloxy}-pyrimidin4-yl)-acetonitrile(3TFA)

Y=22%, M⁺(ES): 500.92; HPLC (Conditions b, max plot) 99.3%, rt. 2.03min.

¹H NMR (DMSO-d6) δ 7.93 (d, J=7.9 Hz, 1H), 7.86 (very br d, 1H), 7.74(br d, 1H), 7.58 (br d, 2H), 7.43-7.36 (m, 3H), 7.28-7.23 (m, 1H), 6.71(br d, 1H), 5.69 (s, 2H), 4.20-3.60 (m, 4H), 3.70-3.67 (m, 2H),3.52-3.34 (m, 2H), 3.20-2.92 (m, 4H)

[4-(4-{4-[(3H-Benzothiazol-2-ylidene)-cyano-methyl]-pyrimidin-2-yloxymethyl}-benzyl)-piperazin-1-yl]-aceticacid methyl ester (3TFA)

Y=14%, M⁺(ES): 528.85; HPLC (Conditions b, max plot) 98%, rt. 2.38 min.

¹H NMR (DMSO-d6) δ 7.94-7.91 (m, 2H), 7.73 (br d, 1H), 7.65 (d, J=7.9Hz, 2H), 7.53 (d, J=7.9 Hz, 2H), 7.44-7.39 (m, 1H), 7.28-7.23 (m, 2H),6.71 (br d, 1H), 5.72 (s, 2H), 4.30 (br s, 2H), 3.62 (s, 3H), 3.49-3.36(m, 2H), 3.30-3.15 (m, 2H), 3.10-2.85 (m, 4H),2.73-2.54 (m, 2H)

2-[4-{4-[(3H-Benzothiazol-2-ylidene)-cyano-methyl]-pyrimidin-2-yloxymethyl}-benzyl)-piperazine-1-yl]-acetamide(3TFA)

Y=16%, M⁺(ES): 513.95; HPLC (Conditions b, max plot) 93%, rt. 2.08 min.

¹H NMR (DMSO-d6) δ 7.93 (d, J=7.9 Hz, 1H), 7.88 (br d, 1H), 7.73 (d,J=7.9 Hz, 1H), 7.61 (d, J=7.9 Hz, 2H), 7.46 (br d, 2H), 7.45-7.40 (m,1H), 7.28-7.23 (m, 1H), 6.72 (br d, 1H), 5.71 (s, 2H), 4.30-2.65 (m,12H)

EXAMPLE 11 Preparation of a Pharmaceutical Formulation

The following formulation examples illustrate representativepharmaceutical compositions according to the present invention being notrestricted thereto.

Formulation 1—Tablets

A piperazine benzothiazole compound of formula I is admixed as a drypowder with a dry gelatin binder in an approximate 1:2 weight ration. Aminor amount of magnesium stearate is added as a lubricant The mixtureis formed into 240-270 mg tablets (80-90 mg of active piperazinebenzothiazole compound per tablet) in a tablet press.

Formulation 2—Capsules

A piperazine benzothiazole compound of formula I is admixed as a drypowder with a starch diluent in an approximate 1:1 weight ratio. Themixture is filled into 250 mg capsules (125 mg of active piperazinebenzothiazole compound per capsule).

Formulation 3—Liquid

A piperazine benzothiazole compound of formula I (1250 mg), sucrose(1.75 g) and xanthan gum (4 mg) are blended, passed through a No. 10mesh U.S. sieve, and then mixed with a previously prepared solution ofmicrocrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50mg) in water. Sodium benzoate (10 mg), flavor, and color are dilutedwith water and added with stirring. Sufficient water is then added toproduce a total volume of 5 mL.

Formulation 4—Tablets

A piperazine benzothiazole compound of formula I is admixed as a drypowder with a dry gelatin binder in an approximate 1:2 weight ratio. Aminor amount of magnesium stearate is added as a lubricant The mixtureis formed into 450-900 mg tablets (150-300 mg of active piperazinebenzothiazole compound) in a tablet press.

Formulation 5—Injection

A piperazine benzothiazole compound of formula I is dissolved in abuffered sterile saline injectable aqueous medium to a concentration ofapproximately 5 mg/ml.

EXAMPLE 12 Biological Assays

The compounds of the present invention may be subjected to the followingassays:

a) JNK2 and -3 in vitro assay:

The compounds of the present invention are inhibitors of JNKs, inparticular of JNK2 and 3. The phosphorylation of c-jun by JNK2 or JNK3may be determined by monitoring the incorporation of ³³P into c-junfollowing the protocol below. The inhibitory activity of the compoundsaccording to formula I, towards c-jun phosphorylation through JNK, isdetermined by calculating phosphorylation activity in the presence orabsence of compounds according to formula I.

JNK3 and/or -2 assays are performed in 96 well MTF plates: incubation of0.5 μg of recombinant, pre-activated GST-JNK3 or GST-JNK2 with 1 μg ofrecombinant, biotinylated GST-c-Jun and 2 μM ³³γ-ATP (2 nCi/μl), in thepresence or absence of compounds according to formula I and in areaction volume of 50 μl containing 50 mM Tris-HCl, pH 8.0; 10 mM MgCl₂;1 mM Dithiothreitol, and 100 μM NaVO₄. The incubation is performed for120 min. at R.T. and stopped upon addition of 200 μl of a solutioncontaining 250 μg of Streptavidine-coated SPA beads (Amersham, Inc.)*, 5mM EDTA, 0.1% Triton X-100 and 50 μM ATP, in phosphate saline buffer.

After incubation for 60 minutes at RT, beads are sedimented bycentrifugation at 1500×g for 5 minutes, resuspended in 200 μl of PBScontaining 5 mM EDTA, 0.1% Triton X-100 and 50 μM ATP and theradioactivity measured in a scintillation β counter, followingsedimentation of the beads as described above.

The tested compounds according to formula I display an inhibition (IC₅₀)with regard to JNK3 of less than 10 μM, preferably less than 1 μM andmore preferred less than 0.25 μM.

b) Global Ischemia in Gerbils

The ability of the JNK inhibitors described in formula I to protect celldeath during a stroke event may be assessed using the followingprotocol:

The gerbil bilateral carotid occlusion is a well-described animal modelof acute ischemic stroke and involves relatively easy surgicaltechniques.

The neuronal degeneration in the hippocampus develops over several daysand is often referred as “delayed neuronal death”. In addition, theneurodegeneration observed histologically is obvious and easilyquantified (11). Furthermore, the histopathology seen in the gerbil issimilar to that observed in the hippocampal CA1 region of the humanbrain following a cardiac arrest. Behavior observations, such as memorytests, could even be performed in the case of gerbils. This kind oftests for appreciation of the degree of recovery is not easilymanageable in other models such as in rat whose learning abilities aremuch poorer (12).

The neuroprotective effect according to formula I to protect may beassessed using-the gerbil global ischemia model and such a protocol:

1—Method

Surgery

-   -   Anesthesia with isoflurane (0.5-4%).    -   The common carotid arteries (left and right) are freed from        tissue.    -   Occlusion of the arteries using Bulldog microclamps during 5        min.    -   Removal of clamps (reperfusion)    -   Stabulation of the animals under heating lamp until awake.    -   Stabulation of the animals in the animalry in individual cages.

Sacrifice of the animals

-   -   7 days after ischemia (Decapitation or overdose of        pentobarbital).    -   Sampling of the brain.

Histological parameters

-   -   Freezing of the brain in isopentane (−20° C.)    -   Slicing of the hippocampus using a cryo-microtome (20 μm).    -   Staining with cresyl violet method    -   Evaluation of the lesions (in CA1/CA2 subfields of the        hippocampus) by a modified Gerhard & Boast score (13).        b 2—Treatment

Administration (ip) of the compound according to formula I or thevehicle: 15 min, 24 hours and 48 hours after reperfusion (5-10 min afterthe recovery of the anesthesia).

Standard protocol

A total of 40 animals is employed; said animals are divided into 5groups of 8 animals:

-   -   Group A: control (saline)    -   Groups B-D: test compound is administered at 3 different doses        (10 mg/kg; 20 mg/kg, 40 mg/kg);    -   Group E: reference compound (Orotic acid 3×300 mg/kg, ip).

For the test compound set out in Example 1 (i.e.1,3-benzothiazol-2-yl[2-({4-[(4-methyl-piperazin-1-yl)methyl]-benzyl}oxy)pyrimidin-4-yl]acetonitrile)used in the above described assay at a concentration of 40 mg per kg, aninhibition of neuronal death of about 60% is determined.

c) Assessment of the BBB Passage: Brain and Plasma Sampling

The compounds of the present invention are useful in the treatmentand/or prophylaxis of cerebral ischemic disorders or CNS disorders.Specifically, the compounds of the present invention show a goodcapacity to cross the blood-brain barrier (EBB). The BBB passingcapacity of the compounds according to formulae I or II may be assessedusing the below protocols. The objective of this assay is to quantifythe amount of the test compounds according to formulae I or II in thebrain of rats following i.v. administration.

Six male Crl:CD(SD)Br Sprague Dawley rats (about 8 weeks old and havinga weight of about 300 g) were divided into the 3 following groups:

Group 1

2 animals for i.v. administration (10 mg/kg of test compound of formulaI in 0.9% NaCl for injection). The test compound is administered bysingle dose (dose regimen). The sampling is performed at 0.25 h aftersacrifice.

Group 2

2 animals for i.v. administration (10 mg/kg of test compound of formulaI in 0.9% NaCl for injection). The test compound is administered bysingle dose (dose regimen). The sampling is performed at 0.5 h aftersacrifice.

Group 3

2 animals for i.v. administration (10 mg/kg of test compound of formulaI in 0.9% NaCl for injection). The test compound is administered bysingle dose (dose regimen). The sampling is performed at 1 h aftersacrifice.

At each scheduled killing time, the animals of the corresponding groupare deeply anaesthetised with diethyl ether. The blood for thecorresponding blood samples is collected into heparinised tubes andcentrifuged to remove the blood cells thus providing plasma. Plasmasamples obtained at each sampling time (i.e. at t=0.25 h, 0.5 h, 1 h)from the rats of each group after administration of the test compound offormula (I) are pooled in order to obtain 1 pooled sample per samplingtime per group. Rats are then sacrificed by exsanguination.

For the-brain sampling, the whole brain (cerebrum and cerebellum) of thesacrificed animals is removed. Brain from two animals per sampling time(i.e. at t=0.25 h, 0.5 h, 1 h after administration) are pooled in orderto obtain one pooled sample per sampling time. Each pooled sample ishomogenized in a solvent mixture(acetonitrile/methanol/dimethyl-sulfoxide, 50:48:2 by volume)centrifuged and the supernatant analyzed for the test compound.

Concentrations in plasma samples and brain homogenates are quantifiedaccording to an analytical HPLC-MS/MS method, properly developed for thecompound.

The test compound used in this assay is the one set out in Example 1(i.e.1,3-benzothiazol-2-yl[2-({4-[(4-methylpiperazin-1-yl)methyl]-benzyl}oxy)pyrimidin-4-yl]acetonitrile.

The concentrations of the test compound in plasma and brain homogenatesamples. assayed by HPLC-MS/MS are illustrated in the below Table 1.TABLE 1 Plasma and brain concentrations of the test compound (as Tri-TFAsalt) found after intravenous administration at the dose of 10 mg/kg.Pooled Samples (n = 2) Plasma Brain Brain/Plasma Time (h) ng/ml ng/gratio 0.25 2835 919 0.32 0.5 2158 657 0.30 1 1983 679 0.34

From Table 1, a considerable and sustained passage of the test compoundinto the brain may be seen.

REFERENCES

-   1. Davis, Roger J., Signal Transduction by the JNK Group of MAP    Kinases. Cell, 2000, 103: 239-252.-   2. Gupta, S. et al., Selective interaction of JNK protein kinase    isoforms with transcription factors. The EMBO Journal, 1996,    158(11): 2760-2770.-   3. Dumitru, Calin D. et al. TNF-alpha induction by LPS is regulated    posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell 2000,    103: 1071-1083.-   4Han, Z. et al., C-Jun N-terminal kinase is required for    metalloproteinase expression and joint destruction in inflammatory    arthritis. The Journal of Clinical Investigation 2001, 108    (1):73-81.-   5. Nishina, H., et al. Impaired CD28-mediated interleukin 2    production and proliferation in stress kinase SAPK/ERK1 kinase    (SEKI)/rnitogen-activated protein kinase kinase 4 (MKK4)-deficient T    lymphocytes. Journal of Experimental Medicine 1997, 186(6): 941-953.-   6. Kempiak, Stephan J. et al. The Jun Kinase Cascade is responsible    for activating the CD28 Response element of the IL-2 Promoter: proof    of cross-talk with the IKB Kinase Cascade, The Journal of    Immunology, 1999, 162: 3176-3187.-   7. De la Monte, S. M. et al., Oxygen free radical injury is    sufficient to cause some Alzheimer-type molecular abnormalities in    human CNS neuronal cells. J. Alzheimer's Dis. 2000, 2(3-4):261-281.-   8. Zhu, X, Activation and redistribution of c-Jun N-terminal    kinase/stress activated protein kinase in degenerating neurons in    Alzheimer's disease, Journal of Neurochemistry 2001, 76: 435-441-   9. Xu, L. et al., Assess the in-vivo activation of signal    transduction pathways with Pathdetect® reporting systems, Strategies    2001, 14 (1): 17-19.-   10. Guha, M. and Mackinan, N., LPS induction of gene expression in    human monocytes, Cellular Signalling 2001, 13: 85-94.-   11. Hunter J. L. et al, Animal models of acute ischemic stroke: can    they predict clinically successful neuroprotective drugs? TIPS 1995,    16:123-128.-   12. Block, F., Global Ischemia And Behavioural Deficits, Progress in    Neurobiology 1999, 58: 279-295.-   13. Gerhard S C and Boast C A, Behavioral Neuroscience 1988, 102:    301-303.-   14. Betz et. al, 1994. Blood-Brain-Cerebrospinal Fluid Barriers.    Chapter 32 in Basic Neurochemistry (5th Edition, Eds Siegel, Albers,    Agranoff, Molinoff), pp 681-701.-   15. Goldstein and Betz, 1986. The Blood-Brain Barrier. Scientific    American, September, 1986, pp 74-83.-   16. WO 01/47920

1-10. (canceled)
 11. Piperazine benzothiazole derivatives according toformula I

as well as its tautomers, its geometrical isomers, its optically activeforms as enantiomers, diastereomers and its racemate forms, as well aspharmaceutically acceptable salts thereof, wherein R is selected fromthe group consisting of hydrogen, C₁-C₆-alkyl, C₁-C₆-alkyl aryl,heteroaryl, C₁-C₆-alkyl heteroaryl, C₂-C₆-alkenyl, C₂-C₆-alkenyl aryl,C₂-C₆-alkenyl heteroaryl, C₂-C₆-alkynyl, C₂-C₆-alkynyl aryl,C₂-C₆-alkynyl heteroaryl, C₃-C₈-cycloalkyl, heterocycloalkyl,C₁-C₆-alkyl cycloalkyl, C₁-C₆-alkyl heterocycloalkyl, C₁-C₆-alkylcarboxy, acyl, C₁-C₆-alkyl acyl, acyloxy, C₁-C₆-alkyl acyloxy,C₁-C₆-alkyl alkoxy, alkoxycarbonyl, C₁-C₆-alkyl alkoxycarbonyl,aminocarbonyl, C₁-C₆-alkyl aminocarbonyl, acylamino, C₁-C₆-alkylacylamino, ureido, C₁-C₆-alkyl ureido, amino, C₁-C₆-alkyl amino,sulfonyloxy, C₁-C₆-alkyl sulfonyloxy, sulfonyl, C₁-C₆-alkyl sulfonyl,sulfinyl, C₁-C₆-alkyl sulfinyl, sulfanyl, C₁-C₆-alkyl sulfanyl,sulfonylamino, C₁-C₆-alkyl sulfonylamino and mixtures thereof; R¹ isselected from the group consisting of H, halogen, cyano, nitro, amino,C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkyl-aryl, aryl orheteroaryl, C₁-C₆-alkyl-heteroaryl, —C(O)—OR², —C(O)—R², —C(O)—NR²R²′,—(SO₂)R² and mixtures thereof, with R² and R^(2′) being independentlyselected from the group consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, aryl, heteroaryl, Cl-C₆-alkyl aryl, C₁-C₆-alkylheteroaryl and mixtures thereof; n is an integer from 0 to
 3. 12. Apiperazine benzothiazole derivative according to claim 11, wherein R¹ ishydrogen.
 13. A piperazine benzothiazole derivative according to claim11, wherein R is selected from the group consisting of hydrogen, C₁-C₃alkyl, aminocarbonyl, C₁-C₆-alkyl alkoxycarbonyl, C₁-C₆-alkyl alkoxy,C₁-C₆-alkyl acyloxy, alkoxycarbonyl, C₁-C₆-alkyl aminocarbonyl andmixtures thereof.
 14. A piperazine benzothiazole derivative according toclaim 13, wherein R is H, or C₁-C₃ alkyl, in particular a methyl or anethyl moiety, or C₁-C₆-alkyl alkoxy.
 15. A piperazine benzothiazolederivative according to claim 11, wherein n is
 1. 16. A piperazinebenzothiazole derivative according to claim 11 selected from the groupconsisting of: 1,3benzothiazol-2-yl[2-({4-[(4-methylpiperazin-1-yl)methyl]benzyl}oxy)pyrimidin-4-yl]acetonitrile,1,3benzothiazol-2-yl[2-({4-[(4-benzyl-piperazin-1-yl)methyl]-benzyl}oxy)pyrimidin-4-yl]acetonitrile,1,3benzothiazol-2-yl(2-{[4-(piperazin-1-ylmethyl)benzyl]oxy}pyrimidin-4-yl)acetonitrile,1,3-benzothiazol-2-yl[2-({4-[(4-formylpiperazin-1-yl)methyl]benzyl}oxy)pyrimidin-4-yl]acetonitrile,[2-({4-[(4-acetylpiperazin-1-yl)methyl]benzyl}oxy)pyrimidin-4-yl](1,3-benzothiazol-2-yl)acetonitrile,(3H-Benzothiazol-2-ylidene)-{2-[4-(4-[1,2,4]oxadiazol-3-ylmethyl-piperazin-1-ylmethyl)-benzyloxy]-pyrimidin-4-yl}-acetonitrile,4-(4-{4-[(3H-Benzothiazol-2-ylidene)-cyano-methyl]-pyrimidin-2-yloxymethyl}-benzyl)-piperazine-1-carboxylicacid methyl ester,2-[4-(4-{4-[(3H-Benzothiazol-2-ylidene)-cyano-methyl]-pyrimidin-2-yloxymethyl}-benzyl)-piperazin-1-yl]-acetamide,(2-{4-[4-(2-Amino-acetyl)-piperazin-1-ylmethyl]-benzyloxy}-pyrimidin-4-yl)-(3H-benzothiazol-2-ylidene)-acetonitrile,[4-(4-{4-[(3H-Benzothiazol-2-ylidene)-cyano-methyl]-pyrimidin-2-yloxymethyl}-benzyl)-piperazin-1-yl]-aceticacid methyl ester,(3H-Benzothiazol-2-ylidene)-(2-{4-[4-(2-methoxy-ethyl)-piperazin-1-yhmethyl]-benzyloxy}-pyrimidin-4-yl)-acetonitrile,4-(4-{4-[(3HBenzothiazol-2-ylidene)-cyano-methyl]-pyrimidin-2-yloxymethyl}-benzyl)-piperazine-1-carboxylicacid dimethylamide,(3H-Benzothiazol-2-ylidene)-{2-[4-(4-ethyl-piperazin-1-ylmethyl)-benzyloxy]-prymidin-4-yl}-acetonitrile,(3H-Benzothiazol-2-ylidene)-(2-{4-[4-(2-hydroxy-ethyl)-piperazin-1-ylmethyl]-benzyloxy}-pyrimidin-4-yl)-acetonitrileand mixtures thereof.
 17. A piperazine benzothiazole derivativeaccording to claim 11 for use as a medicament.
 18. A process for themanufacture of a medicament for the treatment of cerebral ischemicdisorders or CNS disorders comprising adding a piperazine benzothiazolederivative according to claim 11 to said medicament.
 19. Process for thepreparation of a piperazine benzothiazole derivative according to claim11, comprising the following step:

whereby R, R¹ and n are as above described.